Mitochondrial metabolic reprogramming controls the induction of immunogenic cell death and efficacy of chemotherapy in bladder cancer.

Although chemotherapeutic agents have been used for decades, the mechanisms of action, mechanisms of resistance, and the best treatment schedule remain elusive. Mitomycin C (MMC) is the gold standard treatment for non-muscle-invasive bladder cancer (NMIBC). However, it is effective only in a subset of patients, suggesting that, aside from cytotoxicity, other mechanisms could be involved in mediating the success of the treatment. Here, we showed that MMC promotes immunogenic cell death (ICD) and in vivo tumor protection. MMC-induced ICD relied on metabolic reprogramming of tumor cells toward increased oxidative phosphorylation. This favored increased mitochondrial permeability leading to the cytoplasmic release of mitochondrial DNA, which activated the inflammasome for efficient IL-1β (interleukin-1β) secretion that promoted dendritic cell maturation. Resistance to ICD was associated with mitochondrial dysfunction related to low abundance of complex I of the respiratory chain. Analysis of complex I in patient tumors indicated that low abundance of this mitochondrial complex was associated with recurrence incidence after chemotherapy in patients with NMIBC. The identification of mitochondria-mediated ICD as a mechanism of action of MMC offers opportunities to optimize bladder cancer management and provides potential markers of treatment efficacy that could be used for patient stratification.

Science translational medicine. 2021 Jan 06 [Epub]

Bianca Oresta, Chiara Pozzi, Daniele Braga, Rodolfo Hurle, Massimo Lazzeri, Piergiuseppe Colombo, Nicola Frego, Marco Erreni, Cristina Faccani, Grazia Elefante, Matteo Barcella, Giorgio Guazzoni, Maria Rescigno

Humanitas Clinical and Research Center-IRCCS, via Manzoni 56, 20089 Rozzano (Milan), Italy., Department of Experimental Oncology, European Institute of Oncology-IRCCS, via Ripamonti 435, 20141 Milan, Italy., Department of Urology, Humanitas Clinical and Research Center-IRCCS, via Manzoni 56, 20089 Rozzano (Milan), Italy., Department of Pathology, Humanitas Clinical and Research Center-IRCCS, via Manzoni 56, 20089 Rozzano (Milan), Italy., Unit of Advanced Optical Microscopy, Humanitas Clinical and Research Center-IRCCS, via Manzoni 56, 20089 Rozzano (Milan), Italy., Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20142 Milan, Italy., Humanitas Clinical and Research Center-IRCCS, via Manzoni 56, 20089 Rozzano (Milan), Italy. .